Lyna Zhang

Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR

Interferon stimulates the expression of a number of genes encoding enzymes with antiviral activities, including myxovirus resistance-1 (MxA), 2-5-oligoadenylate synthetase 1 (OAS-1) and double-stranded RNA-dependent protein kinase (PKR). We examined whether polymorphisms in these genes influenced the outcome of hepatitis C virus (HCV) infection. We observed a lower frequency of the GG genotype at position −88 in the MxA gene promoter in self-limiting HCV infection (OR=0.56; 95% CI: 0.35–0.8; P=0.010) and in nonresponders to therapy (OR=0.49; 95% CI: 0.25–0.95; P=0.020). This genotype predominantly influenced the outcome of treatment in patients with viral genotype 1 (OR=0.22 95% CI: 0.07–0.67; P=0.002). A polymorphism in the 3′-untranslated region of the OAS-1 gene was associated with outcome of infection (GG genotype less frequent in self-limiting infection: OR=0.43; 95% CI: 0.21–0.86; P=0.010). A polymorphism at position −168 in the promoter region of the PKR gene was associated with self-limiting infection (CT genotype: OR=2.75; 95% CI: 1.45–5.24; P=0.002). Further associations were found with a CGG trinucleotide repeat in the 5′UTR region of the PKR gene. Polymorphisms in the interferon-induced genes, MxA, OAS-1 and PKR appear thus associated with HCV outcome.

Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection

The low-density lipoprotein receptor (LDLR) has been proposed to promote hepatitis C virus endocytosis and the cell membrane protein CD81 may also promote HCV host cell entry. The CD81 gene was sequenced to screen for novel polymorphisms, but no SNPs were identified. Polymorphisms within the LDLR gene are associated with the pathogenesis of familial hypercholesterolemia, atherosclerosis and obesity. We therefore studied genetic variation within the LDLR gene and clinical features of hepatitis C infection. An amino acid change in exon 8 was associated with severity of fibrosis; a SNP in exon 10 correlated with viral clearance and overall inflammation, and a SNP in the 3′UTR appeared to influence treatment response. There were no other significant associations between any of the SNPs studied and the clinical measures of hepatitis C infection. We furthermore report on linkage disequilibrium within the gene and haplotype frequencies in our population. Our findings support a possible role for the LDLR in the modulation of disease progression by affecting immune responses, rather than functioning as receptor for HCV.

Consanguinity and susceptibility to infectious diseases in humans

Studies of animal populations suggest that low genetic heterozygosity is an important risk factor for infection by a diverse range of pathogens, but relatively little research has looked to see whether similar patterns exist in humans. We have used microsatellite genome screen data for tuberculosis (TB), hepatitis and leprosy to test the hypothesis that inbreeding depression increases risk of infection. Our results indicate that inbred individuals are more common among our infected cases for TB and hepatitis, but only in populations where consanguineous marriages are common. No effect was found either for leprosy, which is thought to be oligogenic, or for hepatitis in Italy where consanguineous marriages are rare. Our results suggest that consanguinity is an important risk factor in susceptibility to infectious diseases in humans.

Influence of IL-10RA and IL-22 polymorphisms on outcome of hepatitis C virus infection.

Background: Two receptor chains, IL‐10RA and IL‐10RB, are known to mediate the functions of interleukin‐10 (IL‐10), which has been shown to be involved in the progression of persistent hepatitis C virus (HCV) infection. Little information is available on the role of host genetic variation in IL‐10 receptor genes and outcome of HCV infection. IL‐22, an IL‐10 homologue, shares the IL‐10RB receptor chain with IL‐10 and has antiviral properties. We investigated the possible role of polymorphisms in the IL‐10RA and IL‐22 genes in hepatitis C disease pathogenesis.

Reply to “Apolipoprotein E ε3 and ε4 are associated with Protection against hepatitis E virus in American non‐Hispanic Blacks” by Pischke et al.

We appreciate the attention that Pischke et al. has given to our report. Pischke et al., in averring that anti–hepatitis E virus (HEV) seropositivity is based on lifestyle, seem disposed to exclude the possibility that genetic susceptibility contributes. Host genetic variation influences susceptibility to infectious diseases: why genetic variation would not similarly influence susceptibility toHEV infection or hepatitis E would be puzzling. Pischke et al. suggest further that one-quarter of American Muslims being non-Hispanic blacks confounds our findings as Muslims do not consume porcine food products. The National Health and Nutrition Examination Survey does not collect data on religious affiliation. Further, in 1990 (i.e., about the time the Third National Health and Nutrition Examination Survey was conducted), only an estimated 1% of American, nonHispanic blacks were Muslims. The likelihood of confounding by such a small proportion seems remote. Moreover, Pischke et al. assume thatMuslims, on account of their dietary preferences, are thereby not at risk ofHEV infection. They have not considered that American Muslims may adopt the lifestyles of and share the same environment with other Americans that can expose them to HEV, such as travel to HEV-hyperendemic countries, recreational or occupational contact with HEV-infected animals, and ingestion of water contaminated by HEV shed fecally from infected humans and animals. Pischke et al. state that “Anti-HEV seropositivity reflects a past or present immune response to HEV but is not informative on the host’s response to HEV.” However, the immune response is, per se, a constituent of the host’s response. In bringing up the example of the interleukin28B gene as being able to influence clearance of HCV infection, it becomes apparent that by “host’s response” they mean that which leads to clearance or persistence of infection. Our study, however, concerns identification of a host genetic factor—in this case in or linked to the apolipoprotein E (APOE) gene, which protects against susceptibility to infection (which results in seropositivity), not outcome of infection (which leads to clearance or chronicity). Pischke et al. also suggest that any study on the protective effect of a genetic variant should distinguish between asymptomatic and symptomatic infection. We reiterate that the protection we were studying concerns susceptibility to, not outcome of, infection. Pischke et al. disagree with our consideration that ApoE might protect againstHEV infection from its incorporation in the HEV envelope. This possibility is but one of several possibilities we discussed to explain why ApoE might confer protection. Another, closely related, possibility we presented—that ApoE incorporated into the viral envelope can influence antibody neutralization—finds support in a recently reported study ofHCV. Finally, the further lines of inquiry suggested by Pischke et al. are confined to symptomatic infection and to consumption of porcine food products. They do not consider that HEV infection may not be clinically overt and that (as we have alluded above) adopting lifestyles of and sharing the same environment with fellow members of the population can contribute. Chong-Gee Teo, M.D., Ph.D. Ajay Yesupriya, M.P.H. Man-Huei Chang, M.P.H. Lyna Zhang, M.D., D.Phil. Division of Viral Hepatitis National Center for HIV/AIDS Viral Hepatitis, STD, and TB Prevention Research Data Center National Center for Health Statistics Office of Directors, National Center for HIV/AIDS Viral Hepatitis, STD, and TB Prevention Division of Laboratory Systems Center for Surveillance Epidemiology, and Laboratory Services Centers for Disease Control and Prevention Atlanta, GA